Parkinson's disease is a neurodegenerative disorder characterised by selective degeneration and cell death of dopaminergic neurones in the substantia nigra region of the brainstem. Parkinson's disease is generally considered to be sporadic and of unknown etiology. Over the past five years however, a handful of mutations in the leucine rich repeat kinase 2 (LRRK2) gene have been linked to Parkinson's disease (WO2006068492 and WO2006045392). The G2019S mutation co-segregates with autosomal dominant parkinsonism and accounts for about 6% of familial Parkinson's disease cases and 3% of sporadic Parkinson's disease cases in Europe (Gilks et al., 2005, Lancet, 365: 415-416; Jaleel et al., 2007, Biochem J, 405: 307-317). LRRK2 is a member of the ROCO protein family and all members of this family share five conserved domains. The G2019S mutation occurs in the highly conserved kinase domain and it has therefore been postulated that the G2019S mutation may have an effect on kinase activity (WO2006068492). It has since been verified that this mutation increases the Vmax of LRRK2 for the non-natural, in vitro, substrates, moesin and the LRRKtide peptide (Jaleel et al., 2007, Biochem J, 405: 307-317). Amino acid substitutions at a second residue R1441 are also associated with Parkinson's Disease (reviewed in Paisan-Ruiz 2009, Hum. Mutat. 30: 1153-1160) and have also been shown to elevate LRRK2 kinase activity via decreasing the rate of GTP hydrolysis by the GTPase domain of LRRK2 (Guo et al., 2007 Exp Cell Res. 313: 3658-3670; West et al., 2007 Hum. Mal Gen. 16: 223-232). Over-expression of the mutant protein LRRK2 R1441G is reported to cause symptoms of Parkinson's disease and hyperphosphorylation of Tau in transgenic mouse models (Li, Y. et al. 2009, Nature Neuroscience 12: 826-828). This LRRK2 driven phenotype is also characterised by diminished dopamine release, suggesting that inhibitors of LRRK2 would be expected to positively regulate dopamine release. These data suggest that novel LRRK2 inhibitors of kinase catalytic activity could be useful for the treatment of Parkinson's disease, including idiopathic Parkinson's disease and familial Parkinson's disease, particularly familial Parkinson's disease in patients expressing LRRK2 kinase bearing the G2019S mutation or the R1441G mutation. In addition, LRRK2 inhibitors may have potential utility in treatment of other conditions characterised by diminished dopamine levels such as withdrawal symptoms/relapse associated with drug addiction (Rothman et al., 2008, Prog. Brain Res, 172: 385), and Tauopathy diseases characterised by hyperphosphorylation of Tau such as Alzheimer's disease, argyrophilic grain disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy and inherited frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) (Goedert, M and Jakes, R (2005) Biochemica et Biophysica Acta 1739 240-250).
Two further mutations in LRRK2 have been identified that are clinically associated with the transition from mild cognitive impairment (MCI) to Alzheimer's disease (WO2007149798). These data provide further evidence that inhibitors of LRRK2 kinase activity could be useful for the treatment diseases such as Alzheimer's disease, other dementias and related neurodegenerative disorders.
In an experimental model of Parkinson's disease in marmosets an elevation of LRRK2 mRNA is observed in a manner that correlates with the level of L-Dopa induced dyskinesia (Hurley, M. J et al., 2007 Eur. J. Neurosci. 26: 171-177). This suggests that LRRK2 inhibitors may have utility in amelioration of such dyskinesias.
Evidence is also emerging of roles for LRRK2 in regulating neuronal progenitor differentiation in vitro (Milosevic, J. et al., 2009 Mol. Neurodegen. 4: 25), suggesting that inhibitors of LRRK2 may have utility in production of neuronal progenitor cells in vitro for consequent therapeutic application in cell based-treatment of CNS disorders.
Individuals bearing LRRK2 G2019S mutation have been reported to display increased frequency of non-skin cancers, including renal, breast, lung, prostate cancers as well as acute myelogenous leukemia (AML). Given that G2019S mutation in LRRK2 is reported to increase catalytic activity of the LRRK2 kinase domain, it is anticipated that there may be utility in small molecule inhibitors of LRRK2 for treatment of cancers, especially those of kidney, breast, lung, prostate (e.g. solid tumors) and blood (e.g. AML; Michael J. Fox Foundation for Parkinson's Research, LRRK2 Cohort Workshop, The Desmond Tutu Center, New York City, May 5-6, 2010).
EP1555018 (Institute of Medicinal Molecular Design, Inc.) discloses N-arylsalicylamide derivatives and hydroxyaryl derivatives which are inhibitors of NF-κB activation and AP-1 activation, and their use in the treatment of neurodegenerative diseases such as Alzheimer's disease. Liechti et al., (Eur. J. Med. Chem., 2004, 39: 11-26) discloses a series of salicylanilides and describes their inhibitory activity against tyrosine kinases. McKerrecher et al., (Bioorg. Med. Chem. Lett., 2005, 15(8): 2103-2106) and WO2003000267 (AstraZeneca AB) describe a series of benzamides that are reported to act as activators of glucokinase. WO2001064643 and WO2001064642 (Cor Therapeutics, Inc.) describe a series of benzamides which are stated to act as inhibitors of Factor Xa. JP51029464 (Microbial Chem Res Found) also discloses a series of benzamides. Jensen and Ingvorsen (Acta Chemica Scandinavica, 1952, 6: 161-165) describe the production of amides of 2-benzyloxy-4-nitrobenzoic acid. WO2003084949 describe a series of pyridinoylpiperidine compounds as 5-HT1F agonists, and their use in the treatment of dementia. WO2003078409 (Ono Pharm Co. Ltd) discloses a series of phenylacetic acid derivatives which are stated to be prostaglanding D2 DP receptor antagonists. EP796847 (Shiseido Co Ltd) disclose pyridine derivatives stated to be useful in the treatment of peptic ulcers. WO2006003923 and JP2007176799 (Sankyo Co Ltd) disclose substituted benzene compounds as liver X receptor modulators for use in treating a number of diseases including Alzheimer's disease. WO2007125103 (Novo Nordisk AS) discloses a series of benzamide compounds as glucokinase activators. WO2005000309 (Ionix Pharm Ltd) disclose a series of benzene derivatives as SNS-sodium channel inhibitors. WO2004099170 (Inst. Pharm Discovery LLC) discloses phenyl substituted carboxylic acid compounds as protein tyrosine phosphatase inhibitors. WO9948492 (Japan Tobacco Inc.) discloses amide derivatives as nociceptin antagonists. WO9850030 (Univ Pittsburgh) discloses substituted benzene compounds that are useful in the treatment or prophylaxis of restenosis, intimal hyperplasia associated with restenosis, atherosclerosis and cancer. WO9900121 (Eli Lilly & Co) disclose inhibitors of Factor Xa.